Metabotropic glutamate receptors (mGlus), a class of G-protein coupled receptor (GPCR) family C, have recently emerged as targets of potential therapeutic value. They bind glutamate, an amino acid that is the most prominent excitatory neurotransmitter in the human central nervous system (CNS). mGlus are known to activate biochemical cascades, leading to the modification of other proteins. For example, this can lead to changes in a synapse's excitability by presynaptic inhibition of neurotransmission, or modulation and even induction of postsynaptic responses.
Metabotropic glutamate receptor 3 (mGlu3) is one of eight mGlus that have been identified, and, along with mGlu2, is classified as a group II mGlu. Group II mGlus play an important role is synaptic plasticity, which directly effects cognitive function (including learning and memory), among other things. The effects of group II mGlus occur primarily presynaptically via their inhibition of glutamate release. These effects can also be due to the inhibition of non-vesicular glutamate release from glia. However, group II receptors are known to also reduce the activity of postsynaptic potentials, both excitatory and inhibitory, in the cortex. It is also suggested that mGlu3 is involved with regulating non-synaptic glutamate since it is localized away from active synaptic zones.
Dysfunction of mGlu3 has been implicated in many diseases and/or disorders. Hence, targeting mGlu3 activity has been the subject of much investigation. Several reports have highlighted its link to a variety of diseases, such as cognitive disorders, schizophrenia, depression, Alzheimer's disease, and cancer. Accordingly, there exists a need for modulators of mGlu3.